Mirvetuximab May Replace Paclitaxel as Standard Therapy for High FRα-Expressing Ovarian Cancer

David M. O'Malley, MD

The use of PARP inhibitors to treat ovarian cancers has increased the number of patients who are eligible to receive non-platinum-based therapy. In the case of platinum resistance and sensitivity in patients with folate receptor alpha (FRα)-expressing tumors, research suggests that mirvetuximab soravtansine is an effective treatment option.¹

As a monotherapy, mirvetuximab has achieved confirmed objective responses in 24% to 47% of patients with high FRα tumors. When combined with bevacizumab (Avastin), mirvetuximab has shown a confirmed objective response rate (ORR) of 39% to 56% in patients with medium to high FRα-expressing tumors.

To build on the safety, tolerability, and pharmacokinetic data of mirvetuximab in advanced epithelial ovarian cancer, primary peritoneal, or fallopian tube cancer, a phase 2 study of approximately 311 patients was conducted. At a median follow-up of 17.5 months in the study, the ORR was 47% (95% CI, 34-60) in the overall population of 60 patients and the median duration of response (DOR) was 9.7 months (95% CI, 6.7-12.9).^1,2

Mirvetuximab also shows a median progression-free survival of 8.3 months (95% CI, 5.6-10.6) n the study among patients. Notably, efficacy results in patients who had high FRα-expressing tumors were even better.¹

Patients in the study were stratified by platinum resistance and platinum sensitivity. The safety findings showed that the most common any-grade treatment-related adverse events (AEs) in the platinum-resistant group versus the platinum-sensitive group were diarrhea (68%, 2%), blurred vision (63% vs. 2%), fatigue (58% vs. 7%), and nausea (57% vs. 0%). Grade 3 to 4 AEs that were commonly observed during the study were neutropenia (12% vs. 13%) and hypertension (3% vs. 0%) in the platinum-resistant group versus the platinum-sensitive group, respectively.

In an interview with Targeted Oncology™, David M. O’Malley, MD, a professor in the Department of Obstetrics and Gynecology at The Ohio State University College of Medicine and the director of the Division of Gynecologic Oncology at the OSUCCC – James, discussed the results from an arm of the phase 2 study of 5 mirvetuximab-containing regimens that were evaluated for the treatment of patients with FRα-positive ovarian cancer.

TARGETED ONCOLOGY™: What is the prognosis of patients with platinum-agnostic ovarian cancer. What treatment options are available for these patients?

O’Malley: Patients with platinum-agnostic ovarian cancer are a fairly new group of patients, which we are evaluating in ovarian cancer. The reason for that is there is a growing group of patients who are no longer eligible for platinum due to either hypersensitivity, or intolerance in the past, for example, hematologic toxicity. We're seeing more of these patients that have been classified as platinum-sensitive in the past that are no longer able to get platinum agents, and thus, they're not eligible for clinical trials. So, looking at this group of patients, the overall historical experience is fairly limited, meaning we don't have strong data as we do in classic platinum-resistant ovarian cancer or platinum-sensitive ovarian cancer. Previously, these patients who are not eligible for platinum would just be treated with non-platinum agents on their own or with bevacizumab.

Can you describe the mechanism of action of mirvetuximab and what was the rationale for its use in this patient population?

Mirvetuximab is an antibody-drug conjugate that is targeted to the FRα. It is then internalized, and the payload or the active agents DM4, which is a strong anti-micro tubulin agent.

The rationale is that we saw an increasing number of patients who are not eligible for platinum, though they weren't eligible for other clinical trials, and so we wanted to give those patients an option to have access to the drug. We wanted to see the response with nontoxic mirvetuximab in not only the classically platinum-resistant patients, but also patients who in the past would have been classified as platinum-sensitive but were not eligible for platinum agents and thus not eligible for other clinical trials.

What was the design of this study?

The study design is a straightforward single-arm phase 2 design with Platt with mirvetuximab at 6 milligrams per kilogram with adjusted ideal body weight plus bevacizumab at 50 milligrams per kilogram. Both of those drugs were given intravenously every 3 weeks. We allowed 1 to 3 prior therapies with medium and high expressing FRα. We allowed previous bevacizumab and we allowed previous use of PARP in these in this patient population.

What are the most recent results reported from this study?

We saw in the entire population of 60 patients an overall response rate of 50%. When we look at it at high expression FRα, which was about half the patient population versus low, we see the response rates are even more pronounced at 64% in the high FRα patients. When we look at patient populations and differentiate the high FRα, and then look at platinum sensitivity versus platinum resistance, we see similar objective response rates at approximately 69% in the platinum-sensitive population and 59% in the platinum-resistant population in those high FRα.

The very exciting thing is we see these durations of response persist with more than 12 months duration of response and our high FRα patients who are platinum-sensitive and approaching 10 months with platinum-resistant ovarian cancer patients who are high FRα.

Looking at even those who were medium, we see that the duration response of 8 months, which probably the most exciting result is that 32 of the 33 patients with high FRα had a clinical benefit and beyond the clinical benefit there was tumor shrinkage.

What are the implications of these findings?

The implications of these findings really come down to what I've now said for a couple of year. These data further solidifies that once mirvetuximab is available in the clinics outside of clinical trials that it will replace paclitaxel, in those patients who are high FRα expressors. It adds to the breadth of data that we've seen with mirvetuximab, particularly those with high FRα, of the clinical benefit and the importance of having this agent available to our patients.

What other studies are underway to test mirvetuximab?

Currently, there are 2 studies, which are enrolling or have enrolled. One is called SORAYA, which has recently been completed enrollment and is a single-arm trial of mirvetuximab looking at those with previous expression 1 to 3 prior treatments. Hopefully, we'll be able to see the results of that trial shortly. The other ongoing trial is MIRASOL, which is a large phase 3 trial of single-agent mirvetuximab versus physician’s choice to include paclitaxel, topotecan, or pegylated liposomal doxorubicin. That trial is ongoing and enrolling across the world as a confirmatory trial to SORAYA as well as a worldwide registration pathway. It's important to know both of those trials only enrolled patients with high FRα expression, which will be approximately 40% of patients with high-grade ovarian cancer.

_Reference:

_{1. O’Malley DM, Oaknin A, Matulonis UA, et al. Mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients (pts) with platinum-agnostic ovarian cancer: Final analysis. J Clin Oncol. 2021;39(suppl 15:abstr 5504). doi: 10.1200/JCO.2021.39.15_suppl.5504}

_{2. Study of Mirvetuximab soravtansine in combination with bevacizumab, carboplatin, pegylated liposomal doxorubicin, pembrolizumab, or bevacizumab + carboplatin in participants with folate receptor alpha (FRα) positive advanced epithelial ovarian cancer, primary peritoneal, or fallopian tube cancer. Clinicaltrials.gov. Accessed August 10, 2021.}